■性别差异生物学可能有助于自闭症谱系障碍(ASD)的男性偏见患病率。大脑中男性和女性之间的基因表达差异可以表明可能涉及的分子和细胞机制,尽管人类产前皮质发育过程中的转录组性别差异尚未完全表征,主要是由于样本量小。
■我们在2个独立的批量RNA测序数据集中对性别差异表达和共表达网络分析进行了荟萃分析,这些数据来自273名产前供体的皮质,没有已知的神经精神疾病。为了评估神经典型的性别差异和神经精神障碍生物学之间的交集,我们测试了ASD相关风险基因的富集和表达变化,神经精神疾病风险基因,和鉴定的性别差异表达基因(性别-DEG)和性别差异共表达模块内的细胞类型标记。
■我们确定了101个重要的性别DEG,包括Y染色体基因,受X染色体失活影响的基因,和常染色体基因。已知的ASD风险基因,牵涉到常见或罕见的变异,不优先与性别DEGs重叠。我们鉴定了1个针对免疫信号传导富集的男性特异性共表达模块,其是1个输入数据集特有的。
■性别差异基因的表达在产前人类皮质组织中受到限制,虽然大型数据集的荟萃分析允许识别性别DEG,包括编码参与神经发育的蛋白质的常染色体基因。产前皮质中缺乏与ASD风险基因的性别-DEG重叠,这表明ASD症状的性别差异调节可能发生在其他大脑区域。在其他发展阶段,或者在特定的细胞类型中,或者可能涉及携带突变基因下游的机制。
男性比女性更常被诊断为自闭症谱系障碍,大脑发育的性别差异可能会导致这种差异。这里,我们定义了273个供体的人类产前脑组织中男性和女性之间基因表达模式的差异,以鉴定出101个在男性和女性中表达水平不同的基因,以及显示性别特异性表达相关性的基因集。与自闭症相关的DNA变异基因和自闭症中表达改变的基因不优先与性别差异基因重叠。这表明性别差异生物学可能会影响其他大脑区域的自闭症风险机制,在其他发展阶段,或特定细胞类型。
UNASSIGNED: Sex-differential biology may contribute to the consistently male-biased prevalence of autism spectrum disorder (ASD). Gene expression differences between males and females in the brain can indicate possible molecular and cellular mechanisms involved, although transcriptomic sex differences during human prenatal cortical development have been incompletely characterized, primarily due to small sample sizes.
UNASSIGNED: We performed a meta-analysis of sex-differential expression and co-expression network analysis in 2 independent bulk RNA sequencing datasets generated from cortex of 273 prenatal donors without known neuropsychiatric disorders. To assess the intersection between neurotypical sex differences and neuropsychiatric disorder biology, we tested for enrichment of ASD-associated risk genes and expression changes, neuropsychiatric disorder risk genes, and cell type markers within identified sex-differentially expressed genes (sex-DEGs) and sex-differential co-expression modules.
UNASSIGNED: We identified 101 significant sex-DEGs, including Y-chromosome genes, genes impacted by X-chromosome inactivation, and autosomal genes. Known ASD risk genes, implicated by either common or rare variants, did not preferentially overlap with sex-DEGs. We identified 1 male-specific co-expression module enriched for immune signaling that is unique to 1 input dataset.
UNASSIGNED: Sex-differential gene expression is limited in prenatal human cortex tissue, although meta-analysis of large datasets allows for the identification of sex-DEGs, including autosomal genes that encode proteins involved in neural development. Lack of sex-DEG overlap with ASD risk genes in the prenatal cortex suggests that sex-differential modulation of ASD symptoms may occur in other brain regions, at other developmental stages, or in specific cell types, or may involve mechanisms that act downstream from mutation-carrying genes.
Males are more commonly diagnosed with autism spectrum disorder than females, and sex differences in brain development may contribute to this difference. Here, we define differences in gene expression patterns between males and females in human prenatal brain tissue from 273 donors to identify 101 genes that are expressed at different levels in males and females and gene sets that show sex-specific expression correlations. Genes with autism-associated DNA variants and genes with altered expression in autism do not preferentially overlap with sex-differential genes, suggesting that sex-differential biology may influence autism risk mechanisms in other brain regions, at other developmental stages, or in specific cell types.